Despite the dual role for TGF-beta as both tumor suppressor and tumor promoter in carcinogenesis, preclinical data from our lab and others has previously suggested that strategies to antagonize TGF-beta may selectively reduce the undesirable tumor promoting effects of this growth factor, while sparing the desirable effects on tumor suppression and normal homeostasis. Based on these promising preclinical results, an anti-TGF-beta antibody is in early phase clinical trials for the treatment of advanced cancer (NCI-06-C-0200). However, given the complex biology of TGF-beta, the successful development of TGF-beta antagonists for cancer therapy will depend on a clear understanding of how these agents work, and the related question of how to select patients who will benefit from this type of treatment. In FY09, we have approached this question from a number of angles. As part of our initiative to identify patients who might benefit from treatment with therapeutic anti-TGF-beta antibodies, we have examined the relationship between TGF-beta pathway components and clinical/pathological features using tissue microarrays representing over 800 breast cancer cases, in collaboration with Dr. Mark Sherman, DCEG, NCI. The data provide evidence for multiple complex biologic effects of the TGF-beta pathway on breast cancer development. One striking finding is that TGF-beta pathway activation decreases dramatically with age, a feature that may contribute to the differing behavior of histologically similar tumors in old and young patients. We are continuing to apply global and candidate gene expression analysis, molecular histology, immunophenotyping and immunodepletion approaches to understanding the metastasis suppressing effect of anti-TGF-beta antibody treatment in a variety of syngeneic mouse transplantation models of metastatic breast cancer. We have established a panel of models showing differing responses to TGF-beta antagonism in vivo, from which we hope to identify molecular determinants of therapeutic vs adverse response/resistance to anti-TGF-beta antibodies. Such information should be helpful in patient selection for clinical trials. We have shown that treatment with paclitaxel and anti-TGF-beta can synergize to suppress metastasis, and we are optimizing drug scheduling and sequencing, as well as addressing underlying mechanisms with a particular focus on the anti-tumor immune response